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Lamictal XR

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Lamictal XR

CLINICAL PHARMACOLOGY

Mechanism Of Action

The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action is unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure spread in the maximum electroshock and pentylenetetrazol tests, and prevented seizures in the visually and electrically evoked after-discharge tests for antiepileptic activity. Lamotrigine also displayed inhibitory properties in a kindling model in rats both during kindling development and in the fully kindled state. The relevance of these models to human epilepsy, however, is not known.

One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).

Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity

Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced currents (in the presence of 3 ÁM of glycine) in cultured hippocampal neurons exceeded 100 ÁM.

Pharmacodynamics

Folate Metabolism

In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and maternal folate concentrations were reduced. Significantly reduced concentrations of folate are associated with teratogenesis [see Use In Specific Populations]. Folate concentrations were also reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were partially returned to normal when supplemented with folinic acid.

Cardiovascular

In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes dose-dependent prolongation of the PR interval, widening of the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite ( < 0.6% of lamotrigine dose) have been found in human urine. However, it is conceivable that plasma concentrations of this metabolite could be increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in patients with liver disease, patients taking concomitant medications that inhibit glucuronidation).

Pharmacokinetics

In comparison to immediate-release lamotrigine, the plasma lamotrigine levels following administration of LAMICTAL XR are not associated with any significant changes in trough plasma concentrations, and are characterized by lower peaks, longer time to peaks, and lower peak-to-trough fluctuation, as described in detail below.

Absorption

Lamotrigine is absorbed after oral administration with negligible first-pass metabolism. The bioavailability of lamotrigine is not affected by food.

In an open-label, crossover study of 44 subjects with epilepsy receiving concomitant AEDs, the steady-state pharmacokinetics of lamotrigine were compared following administration of equivalent total doses of LAMICTAL XR given once daily with those of lamotrigine immediate-release given twice daily. In this study, the median time to peak concentration (Tmax) following administration of LAMICTAL XR was 4 to 6 hours in patients taking carbamazepine, phenytoin, phenobarbital, or primidone; 9 to 11 hours in patients taking valproate; and 6 to 10 hours in patients taking AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate. In comparison, the median Tmax following administration of immediate-release lamotrigine was between 1 and 1.5 hours.

The steady-state trough concentrations for extended-release lamotrigine were similar to or higher than those of immediate-release lamotrigine depending on concomitant AED (Table 6). A mean reduction in the lamotrigine Cmax by 11% to 29% was observed for LAMICTAL XR compared to immediate-release lamotrigine, resulting in a decrease in the peak-to-trough fluctuation in serum lamotrigine concentrations. However, in some subjects receiving enzymeinducing AEDs, a reduction in Cmax of 44% to 77% was observed. The degree of fluctuation was reduced by 17% in patients taking enzyme-inducing AEDs; 34% in patients taking valproate; and 37% in patients taking AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate. LAMICTAL XR and immediate-release lamotrigine regimens were similar with respect to area under the curve (AUC, a measure of the extent of bioavailability) for patients receiving AEDs other than those known to induce the metabolism of lamotrigine. The relative bioavailability of extended-release lamotrigine was approximately 21% lower than immediaterelease lamotrigine in subjects receiving enzyme-inducing AEDs. However, a reduction in exposure of up to 70% was observed in some subjects in this group when they switched to LAMICTAL XR. Therefore, doses may need to be adjusted in some subjects based on therapeutic response.

Table 6: Steady-State Bioavailability of LAMICTAL XR Relative to Immediate-Release Lamotrigine at Equivalent Daily Doses (Ratio of Extended-Release to Immediate-Release 90% CI)

Concomitant Antiepileptic Drug AUC
(0-24ss)
Cmax Cmin
Enzyme-inducing antiepileptic drugsa 0.79
(0.69, 0.90)
0.71
(0.61, 0.82)
0.99
(0.89, 1.09)
Valproate 0.94
(0.81, 1.08)
0.88
(0.75, 1.03)
0.99
(0.88, 1.10)
Antiepileptic drugs other than enzyme-inducing antiepileptic drugsa or valproate 1.00
(0.88, 1.14)
0.89
(0.78, 1.03)
1.14
(1.03, 1.25)
a Enzyme-inducing antiepileptic drugs include carbamazepine, phenytoin, phenobarbital, and primidone.

Dose Proportionality

In healthy volunteers not receiving any other medications and given LAMICTAL XR once daily, the systemic exposure to lamotrigine increased in direct proportion to the dose administered over the range of 50 to 200 mg. At doses between 25 and 50 mg, the increase was less than dose proportional, with a 2-fold increase in dose resulting in an approximately 1.6-fold increase in systemic exposure.

Distribution

Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers.

Protein Binding

Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other drugs through competition for protein binding sites are unlikely. The binding of lamotrigine to plasma proteins did not change in the presence of therapeutic concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other AEDs (carbamazepine, phenytoin, phenobarbital) from protein-binding sites.

Metabolism

Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of 14C-lamotrigine (15 ÁCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).

Enzyme Induction

The effects of lamotrigine on the induction of specific families of mixed-function oxidase isozymes have not been systematically evaluated.

Following multiple administrations (150 mg twice daily) to normal volunteers taking no other medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in ty2 and a 37% increase in CL/F at steady state compared with values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see DRUG INTERACTIONS].

Elimination

The elimination half-life and apparent clearance of lamotrigine following oral administration of immediate-release lamotrigine to adult patients with epilepsy and healthy volunteers is summarized in Table 7. Half-life and apparent clearance vary depending on concomitant AEDs.

Since the half-life of lamotrigine following administration of single doses of immediaterelease lamotrigine is comparable to that observed following administration of LAMICTAL XR, similar changes in the half-life of lamotrigine would be expected for LAMICTAL XR.

Table 7: Meana Pharmacokinetic Parameters of Immediate-Release Lamotrigine in Healthy Volunteers and Adult Patients With Epilepsy

Adult Study Population Number of Subjects t½ Elimination Halflife
(hr)
CL/F: Apparent Plasma Clearance
(mL/min/kg)
Healthy volunteers taking no other medications:
  Single-dose lamotrigine 179 32.8
(14.0-103.0)
0.44
(0.12-1.10)
  Multiple-dose lamotrigine 36 25.4
(11.6-61.6)
0.58
(0.24-1.15)
Healthy volunteers taking valproate:
  Single-dose lamotrigine 6 48.3
(31.5-88.6)
0.30
(0.14-0.42)
  Multiple-dose lamotrigine 18 70.3
(41.9-113.5)
0.18
(0.12-0.33)
Patients with epilepsy taking valproate only:
  Single-dose lamotrigine 4 58.8
(30.5-88.8)
0.28
(0.16-0.40)
Patients with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidoneb plus valproate:
  Single-dose lamotrigine 25 27.2
(11.2-51.6)
0.53
(0.27-1.04)
Patients with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone:b
  Single-dose lamotrigine 24 14.4
(6.4-30.4)
1.10
(0.51-2.22)
  Multiple-dose lamotrigine 17 12.6
(7.5-23.1)
1.21
(0.66-1.82)
a The majority of parameter means determined in each study had coefficients of variation between 20% and 40% for half-life and CL/F and between 30% and 70% for Tmax. The overall mean values were calculated from individual study means that were weighted based on the number of volunteers/patients in each study. The numbers in parentheses below each parameter mean represent the range of individual volunteer/patient values across studies.
b Carbamazepine, phenobarbital, phenytoin, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs such as rifampin that induce lamotrigine glucuronidation have also been shown to increase the apparent clearance of lamotrigine [see DRUG INTERACTIONS].

Drug Interactions

The apparent clearance of lamotrigine is affected by the coadministration of certain medications [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].

The net effects of drug interactions with lamotrigine are summarized in Table 8. Details of the drug interaction studies, which were done using immediate-release lamotrigine, are provided in Table 8.

Table 8: Summary of Drug Interactions With Lamotrigine

Drug Drug Plasma Concentration With Adjunctive Lamotriginea Lamotrigine Plasma Concentration With Adjunctive Drugsb
Oral contraceptives (e.g.,ethinylestradiol/levonorgestrelc) d
Bupropion Not assessed
Carbamazepine
Carbamazepine epoxidee ?
Felbamate Not assessed
Gabapentin Not assessed
Levetiracetam
Lithium Not assessed
Olanzapine f
Oxcarbazepine
10-monohydroxy oxcarbazepine metaboliteg
Phenobarbital/primidone
Phenytoin
Pregabalin
Rifampin Not assessed
Topiramate h
Valproate ↓ 
Valproate + phenytoin and/or carbamazepine Not assessed
Zonisamide Not assessed
a From adjunctive clinical trials and volunteer studies.
b Net effects were estimated by comparing the mean clearance values obtained in adjunctive clinical trials and volunteer studies.
c The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials, although the effect may be similar to that seen with the ethinylestradiol/levonorgestrel combinations.
d Modest decrease in levonorgestrel.
e Not administered, but an active metabolite of carbamazepine.
fSlight decrease, not expected to be clinically relevant.
g Not administered, but an active metabolite of oxcarbazepine.
h Slight increase, not expected to be clinically relevant.
↔= No significant effect.
? = Conflicting data.

Estrogen-Containing Oral Contraceptives

In 16 female volunteers, an oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by approximately 2-fold with mean decreases in AUC of 52% and in Cmax of 39%. In this study, trough serum lamotrigine concentrations gradually increased and were approximately 2-fold higher on average at the end of the week of the inactive hormone preparation compared with trough lamotrigine concentrations at the end of the active hormone cycle.

Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase) occurred during the week of inactive hormone preparation (pill-free week) for women not also taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation) [see DRUG INTERACTIONS]. The increase in lamotrigine plasma levels will be greater if the dose of LAMICTAL XR is increased in the few days before or during the pill-free week. Increases in lamotrigine plasma levels could result in dose-dependent adverse reactions.

In the same study, coadministration of lamotrigine (300 mg/day) in 16 female volunteers did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive preparation. There were mean decreases in the AUC and Cmax of the levonorgestrel component of 19% and 12%, respectively. Measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamicpituitary- ovarian axis.

The effects of doses of lamotrigine other than 300 mg/day have not been systematically evaluated in controlled clinical trials.

The clinical significance of the observed hormonal changes on ovulatory activity is unknown. However, the possibility of decreased contraceptive efficacy in some patients cannot be excluded. Therefore, patients should be instructed to promptly report changes in their menstrual pattern (e.g., break-through bleeding).

Dosage adjustments may be necessary for women receiving estrogen-containing oral contraceptive preparations [see DOSAGE AND ADMINISTRATION].

Other Hormonal Contraceptives or Hormone Replacement Therapy

The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of LAMICTAL XR in the presence of progestogens alone will likely not be needed.

Bupropion

The pharmacokinetics of a 100-mg single dose of lamotrigine in healthy volunteers (n = 12) were not changed by coadministration of bupropion sustained-release formulation (150 mg twice daily) starting 11 days before lamotrigine.

Carbamazepine

Lamotrigine has no appreciable effect on steady-state carbamazepine plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in patients receiving carbamazepine with lamotrigine than in patients receiving other AEDs with lamotrigine [see ADVERSE REACTIONS]. The mechanism of this interaction is unclear. The effect of lamotrigine on plasma concentrations of carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a placebocontrolled trial, lamotrigine had no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels increased.

The addition of carbamazepine decreases lamotrigine steady-state concentrations by approximately 40%.

Esomeprazole

In a study of 30 subjects, coadministration of LAMICTAL XR with esomeprazole resulted in no significant change in lamotrigine levels and a small decrease in Tmax. The levels of gastric pH were not altered compared with pre-lamotrigine dosing.

Felbamate

In a study of 21 healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine.

Folate Inhibitors

Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism.

Gabapentin

Based on a retrospective analysis of plasma levels in 34 patients who received lamotrigine both with and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine.

Levetiracetam

Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating serum concentrations of both agents during placebo-controlled clinical trials. These data indicate that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine.

Lithium

The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by coadministration of lamotrigine (100 mg/day) for 6 days.

Olanzapine

The AUC and Cmax of olanzapine were similar following the addition of olanzapine (15 mg once daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 16) compared with the AUC and Cmax in healthy male volunteers receiving olanzapine alone (n = 16).

In the same study, the AUC and Cmax of lamotrigine were reduced on average by 24% and 20%, respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers compared with those receiving lamotrigine alone. This reduction in lamotrigine plasma concentrations is not expected to be clinically relevant.

Oxcarbazepine

The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite were not significantly different following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 13) compared with healthy male volunteers receiving oxcarbazepine alone (n = 13).

In the same study, the AUC and Cmax of lamotrigine were similar following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine in healthy male volunteers compared with those receiving lamotrigine alone. Limited clinical data suggest a higher incidence of headache, dizziness, nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine compared with lamotrigine alone or oxcarbazepine alone.

Phenobarbital, Primidone

The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by approximately 40%.

Phenytoin

Lamotrigine has no appreciable effect on steady-state phenytoin plasma concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steadystate concentrations by approximately 40%.

Pregabalin

Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic interactions between lamotrigine and pregabalin.

Rifampin

In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent clearance of a single 25-mg dose of lamotrigine by approximately 2-fold (AUC decreased by approximately 40%).

Topiramate

Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.

Valproate

When lamotrigine was administered to healthy volunteers (n = 18) receiving valproate, the trough steady-state valproate plasma concentrations decreased by an average of 25% over a 3-week period, and then stabilized. However, adding lamotrigine to the existing therapy did not cause a change in valproate plasma concentrations in either adult or pediatric patients in controlled clinical trials.

The addition of valproate increased lamotrigine steady-state concentrations in normal volunteers by slightly more than 2-fold. In one study, maximal inhibition of lamotrigine clearance was reached at valproate doses between 250 and 500 mg/day and did not increase as the valproate dose was further increased.

Zonisamide

In a study of 18 patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with lamotrigine (150 to 500 mg/day for 35 days) had no significant effect on the pharmacokinetics of lamotrigine.

Known Inducers or Inhibitors of Glucuronidation

Drugs other than those listed above have not been systematically evaluated in combination with lamotrigine. Since lamotrigine is metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of LAMICTAL XR may require adjustment based on clinical response.

Other

Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone.

Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6.

Special Populations

Patients With Renal Impairment: Twelve volunteers with chronic renal failure (mean creatinine clearance: 13 mL/min, range: 6 to 23) and another 6 individuals undergoing hemodialysis were each given a single 100-mg dose of immediate-release lamotrigine. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared with 26.2 hours in healthy volunteers. On average, approximately 20% (range: 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour session [see DOSAGE AND ADMINISTRATION].

Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose of immediate-release lamotrigine were evaluated in 24 subjects with mild, moderate, and severe hepatic impairment (Child-Pugh Classification system) and compared with 12 subjects without hepatic impairment. The patients with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5). The mean apparent clearances of lamotrigine in patients with mild (n = 12), moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment were 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared with 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-lives of lamotrigine in patients with mild, moderate, severe without ascites, and severe with ascites hepatic impairment were 46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared with 33 ± 7 hours in healthy controls [see DOSAGE AND ADMINISTRATION].

Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of immediate-release lamotrigine were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean creatinine clearance: 61 mL/min, range: 33 to 108 mL/min). The mean halflife of lamotrigine in these subjects was 31.2 hours (range: 24.5 to 43.4 hours), and the mean clearance was 0.40 mL/min/kg (range: 0.26 to 0.48 mL/min/kg).

Gender: The clearance of lamotrigine is not affected by gender. However, during dose escalation of immediate-release lamotrigine in one clinical trial in patients with epilepsy on a stable dose of valproate (n = 77), mean trough lamotrigine concentrations, unadjusted for weight, were 24% to 45% higher (0.3 to 1.7 mcg/mL) in females than in males.

Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than Caucasians.

Pediatric Patients: Safety and effectiveness of LAMICTAL XR for use in patients less than 13 years of age have not been established.

Clinical Studies

Adjunctive Therapy For Primary Generalized Tonic-Clonic Seizures

The effectiveness of LAMICTAL XR as adjunctive therapy was established in PGTC seizures in a 19-week, international, multicenter, double-blind, randomized, placebo-controlled study in 143 patients 13 years of age and older (n = 70 on LAMICTAL XR and n = 73 on placebo). Patients with at least 3 PGTC seizures during an 8-week baseline phase were randomized to 19 weeks of treatment with LAMICTAL XR or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed on a fixed-dose regimen, with target doses ranging from 200 to 500 mg/day of LAMICTAL XR based on concomitant AED(s) (target dose = 200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine levels, and 500 mg for enzyme-inducing AEDs).

The primary efficacy endpoint was percent change from baseline in PGTC seizure frequency during the double-blind treatment phase. For the intent-to-treat population, the median percent reduction in PGTC seizure frequency was 75% in patients treated with LAMICTAL XR and 32% in patients treated with placebo, a difference that was statistically significant, defined as a 2-sided P value ≤ 0.05.

Figure 1 presents the percentage of patients (X-axis) with a percent reduction in PGTC seizure frequency (responder rate) from baseline through the entire treatment period at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in PGTC seizure frequency was consistently higher for the group treated with LAMICTAL XR compared with the placebo group. For example, 70% of patients randomized to LAMICTAL XR experienced a 50% or greater reduction in PGTC seizure frequency, compared with 32% of patients randomized to placebo. Patients with an increase in seizure frequency > 100% are represented on the Y-axis as equal to or greater than -100%.

Figure 1: Proportion of Patients by Responder Rate for LAMICTAL XR and Placebo Group (Primary Generalized Tonic-Clonic Seizures Study)

Proportion of Patients by Responder Rate for LAMICTAL XR and Placebo Group - Illustration

Adjunctive Therapy For Partial Onset Seizures

The effectiveness of immediate-release lamotrigine as adjunctive therapy was initially established in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial onset seizures.

The effectiveness of LAMICTAL XR as adjunctive therapy in partial onset seizures, with or without secondary generalization, was established in a 19-week, multicenter, double-blind, placebo-controlled trial in 236 patients 13 years of age and older (approximately 93% of patients were aged 16 to 65 years). Approximately 36% were from the U.S. and approximately 64% were from other countries including Argentina, Brazil, Chile, Germany, India, Korea, Russian Federation, and Ukraine. Patients with at least 8 partial onset seizures during an 8-week prospective baseline phase (or 4-week prospective baseline coupled with a 4-week historical baseline documented with seizure diary data) were randomized to treatment with LAMICTAL XR (n = 116) or placebo (n = 120) added to their current regimen of 1 or 2 AEDs. Approximately half of the patients were taking 2 concomitant AEDs at baseline. Target doses ranged from 200 to 500 mg/day of LAMICTAL XR based on concomitant AED (target dose = 200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine, and 500 mg for enzyme-inducing AEDs). The median partial seizure frequency per week at baseline was 2.3 for LAMICTAL XR and 2.1 for placebo.

The primary endpoint was the median percent change from baseline in partial onset seizure frequency during the entire double-blind treatment phase. The median percent reductions in weekly partial onset seizures were 47% in patients treated with LAMICTAL XR and 25% on placebo, a difference that was statistically significant, defined as a 2-sided P value < 0.05.

Figure 2 presents the percentage of patients (X-axis) with a percent reduction in partial seizure frequency (responder rate) from baseline through the entire treatment period at least as great as that represented on the Y-axis. The proportion of patients achieving any particular level of reduction in partial seizure frequency was consistently higher for the group treated with LAMICTAL XR compared with the placebo group. For example, 44% of patients randomized to LAMICTAL XR experienced a 50% or greater reduction in partial seizure frequency compared with 21% of patients randomized to placebo.

Figure 2: Proportion of Patients by Responder Rate for LAMICTAL XR and Placebo Group (Partial Onset Seizure Study)

Proportion of Patients by Responder Rate for LAMICTAL XR and Placebo Group - Illustration

Conversion To Monotherapy For Partial Onset Seizures

The effectiveness of LAMICTAL XR as monotherapy for partial onset seizures was established in a historical-control trial in 223 adults with partial seizures. The historical control methodology is described in a publication by French, et al. [see REFERENCES]. Briefly, in this study, patients were randomized to ultimately receive either LAMICTAL XR 300 mg or 250 mg once a day, and their responses were compared to those of a historical control group. The historical control consisted of a pooled analysis of the control groups from 8 studies of similar design, which utilized a subtherapeutic dose of an AED as a comparator. Statistical superiority to the historical control was considered to be demonstrated if the upper 95% confidence interval for the proportion of patients meeting escape criteria in patients receiving LAMICTAL XR remained below the lower 95% prediction interval of 65.3% derived from the historical control data.

In this study, patients ≥ 13 years of age experienced at least 4 partial seizures during an 8- week baseline period with at least 2 seizures occurring during each of 2 consecutive 4-week periods while receiving valproate or a non-enzyme-inducing AED. LAMICTAL XR was added to either valproate or a non-enzyme-inducing AED over a 6- to 7-week period followed by the gradual withdrawal of the background AED. Patients were then continued on monotherapy with LAMICTAL XR for 12 weeks. The escape criteria were one or more of the following: (1) doubling of average monthly seizure count during any 28 consecutive days, (2) doubling of highest consecutive 2-day seizure frequency during the entire treatment phase, (3) emergence of a new seizure type compared to baseline (4) clinically significant prolongation of generalized tonic-clonic seizures or worsening of seizure considered by the investigator to require intervention. These criteria were similar to those in the 8 controlled trials from which the historical control group was constituted.

The upper 95% confidence limits of the proportion of subjects meeting escape criteria (40.2% at 300 mg/day and 44.5% at 250 mg/day) were below the threshold of 65.3% derived from the historical control data.

Although the study population was not fully comparable to the historical controlled population and the study was not fully blinded, numerous sensitivity analyses supported the primary results. Efficacy was further supported by the established effectiveness of the immediate-release formulation as monotherapy.

REFERENCES

1. French JA, Wang S, Warnock B, Temkin N. Historical control monotherapy design in the treatment of epilepsy. Epilepsia. 2010; 51(10):1936-1943.

Last reviewed on RxList: 1/27/2014
This monograph has been modified to include the generic and brand name in many instances.

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